Whitchurch Hospital

Exosomes are small membrane vesicles found in cell culture supernatants and in different biological fluids. Exosomes form in a particular population of endosomes, called multivesicular bodies (MVBs), by inward budding into the lumen of the compartment. Upon fusion of MVBs with the plasma membrane, these internal vesicles are secreted. Exosomes possess a defined set of membrane and cytosolic proteins. The physiological function of exosomes is still a matter of debate, but increasing results in various experimental systems suggest their involvement in multiple biological processes. Because both cell-culture supernatants and biological fluids contain different types of lipid membranes, it is critical to perform high-quality exosome purification. This unit describes different approaches for exosome purification from various sources, and discusses methods to evaluate the purity and homogeneity of the purified exosome preparations.

In 1984, the 32 member states of the World Health Organization European Region took a remarkable step forward in agreeing unanimously on 38 targets for a common health policy for the Region. Not only was equity the subject of the first of these targets, but it was also seen as a fundamental theme running right through the policy as a whole. However, equity can mean different things to different people. This article looks at the concepts and principles of equity as understood in the context of the World Health Organization's Health for All policy. After considering the possible causes of the differences in health observed in populations--some of them inevitable and some unnecessary and unfair--the author discusses equity in relation to health care, concentrating on issues of access to care, utilization, and quality. Lastly, seven principles for action are outlined, stemming from these concepts, to be borne in mind when designing or implementing policies, so that greater equity in health and health care can be promoted.

A new method for finding the maximum of a general non-linear function of several variables within a constrained region is described, and shown to be efficient compared with existing methods when the required optimum lies on one or more constraints. The efficacy of using effective constraints to eliminate variables is demonstrated, and a program to achieve this easily and automatically is described. Finally, the performance of the new method (the “Complex” method) with unconstrained problems, is compared with those of the Simplex method, from which it was evolved, and Rosenbrock's method.

Excessive drinkers (141) identified in medical settings who were not seeking help for an alcohol problem completed a questionnaire based on Prochaska and DiClemente's stages of change model. Principal components analysis revealed a clear factor structure corresponding to the 'precontemplation', 'contemplation' and 'action' stages of change. On this basis, a 12-item 'Readiness to change' questionnaire was developed with satisfactory psychometric properties. As predicted, scale scores on adjacent stages of change showed significantly higher inter-correlations than scores on non-adjacent stages. Concurrent validation by comparison with subjects' choices of cartoons depicting each of the stages of change and with screening questions regarding aspects of drinking behaviour was moderate to very good. The questionnaire provides a short and convenient measure of readiness to change which may be used in conjunction with brief, opportunistic interventions with excessive drinkers.

Purpose In experimental systems, interference with coagulation can affect tumor biology. Furthermore, it has been suggested that low molecular weight heparin therapy may prolong survival in patients with cancer. The primary aim of this study was to assess survival at 1 year of patients with advanced cancer. Patients and Methods Patients with advanced malignancy (N = 385) were randomly assigned to receive either a once-daily subcutaneous injection of dalteparin (5,000 IU), a low molecular weight heparin, or placebo for 1 year. Results The Kaplan-Meier survival estimates at 1, 2, and 3 years after randomization for patients receiving dalteparin were 46%, 27%, and 21%, respectively, compared with 41%, 18%, and 12%, respectively, for patients receiving placebo (P = .19). In an analysis not specified a priori, survival was examined in a subgroup of patients (dalteparin, n = 55; and placebo, n = 47) who had a better prognosis and who were alive 17 months after randomization. In these patients, Kaplan-Meier survival estimates at 2 and 3 years from randomization were significantly improved for patients receiving dalteparin versus placebo (78% v 55% and 60% v 36%, respectively, P = .03). The rates of symptomatic venous thromboembolism were 2.4% and 3.3% for dalteparin and placebo, respectively, with bleeding rates of 4.7% and 2.7%, respectively. Conclusion Dalteparin administration did not significantly improve 1-year survival rates in patients with advanced malignancy. However, the observed improved survival in a subgroup of patients with a better prognosis suggests a potential modifying effect of dalteparin on tumor biology.

Current management guidelines for the treatment of patients with Parkinson's disease (PD) are limited due to the lack of knowledge of factors that influence health-related quality of life (HRQL). To assess the HRQL of people with PD, and to systematically identify and evaluate those factors (other than disease severity and medication, which could have an impact), we undertook a cross-sectional, randomized selection, multicenter international survey of patients with PD, caregivers, and clinicians. Face-to-face interviews were conducted with subjects in six countries. Disease severity, medication, and other factors hypothesized to influence HRQL were assessed using a combination of specially developed questionnaires and validated instruments including the Parkinson's Disease Questionnaire-39 (HRQL), Hoehn and Yahr Stage (disease severity), and Beck's Depression Inventory (BDI; depression). Multiple linear regression models were used to demonstrate whether the factors investigated contribute significantly to HRQL. The results obtained indicated that Hoehn and Yahr stage and medication explained only 17.3% of the variability in HRQL of patients with PD, although both were significant (R(2) = 0.173, P < 0.05). Other factors increased the explanatory power to adjusted R(2) = 0.597, with BDI being the most significant predictor of variability in HRQL (adjusted R(2) = 0.582; P < 0.001), followed by "Satisfaction with the explanation of the condition at diagnosis" and "Current feelings of optimism" (both P < 0.05). These factors, in addition to disease severity and medication, explain 59.7% of the variability in HRQL across the population. In conclusion, depression (as measured by the BDI) in PD, "satisfaction with the explanation of the condition at diagnosis" and "current feelings of optimism" have a significant impact on HRQL. The completion of this initial analysis is the first step towards developing management guidelines that truly influence the HRQL of patients with PD.

BACKGROUND: To reduce contagion of COVID-19, in March 2020 UK general practices implemented predominantly remote consulting via telephone, video, or online consultation platforms. AIM: To investigate the rapid implementation of remote consulting and explore impact over the initial months of the COVID-19 pandemic. DESIGN AND SETTING: Mixed-methods study in 21 general practices in Bristol, North Somerset and South Gloucestershire. METHOD: Longitudinal observational quantitative analysis compared volume and type of consultation in April to July 2020 with April to July 2019. Negative binomial models were used to identify if changes differed among different groups of patients. Qualitative data from 87 longitudinal interviews with practice staff in four rounds investigated practices' experience of the move to remote consulting, challenges faced, and solutions. A thematic analysis utilised Normalisation Process Theory. RESULTS: There was universal consensus that remote consulting was necessary. This drove a rapid change to 90% remote GP consulting (46% for nurses) by April 2020. Consultation rates reduced in April to July 2020 compared to 2019; GPs and nurses maintained a focus on older patients, shielding patients, and patients with poor mental health. Telephone consulting was sufficient for many patient problems, video consulting was used more rarely, and was less essential as lockdown eased. SMS-messaging increased more than three-fold. GPs were concerned about increased clinical risk and some had difficulties setting thresholds for seeing patients face-to-face as lockdown eased. CONCLUSION: The shift to remote consulting was successful and a focus maintained on vulnerable patients. It was driven by the imperative to reduce contagion and may have risks; post-pandemic, the model will need adjustment.

p53 mutation remains the most common genetic change identified in human neoplasia. In breast cancer, p53 mutation is associated with more aggressive disease and worse overall survival. The frequency of mutation in p53 is, however, lower in breast cancer than in other solid tumours. Changes, both genetic and epigenetic, have been identified in regulators of p53 activity and in some downstream transcriptional targets of p53 in breast cancers that express wild-type p53. Molecular pathological analysis of the structure and expression of constituents of the p53 pathway is likely to have value in diagnosis, in prognostic assessment and, ultimately, in treatment of breast cancer.

Twenty index patients with hereditary essential tremor and their kindreds were studied to define the phenotype of this condition. Ninety-three first degree and 38 more distant relatives were examined; 53 definite and 18 possible secondary cases were identified. The age of tremor onset was bimodally distributed with a median at approximately 15 years. Segregation analysis indicated autosomal dominant inheritance and penetrance was virtually complete by the age of 65 years. There were no examples of the disease skipping a generation. Men and women were affected in equal proportions. About 50% of cases were alcohol responsive. In the majority of families alcohol responsiveness was either consistently present or did not occur, but in 20% of kindreds definite heterogeneity of responsiveness was encountered within each family. The typical phenotype was a mild symmetrical postural tremor of the upper limbs. Tremor of the legs, head, facial muscles, voice, jaw and tongue occurred but never in isolation and rest, task specific (e.g. primary writing tremor) and primary orthostatic tremors were not found. Head tremor was invariably mild and 75% was of a 'no-no' type. Dystonia (e.g. torticollis and writer's cramp) were not encountered, a finding which strongly suggests that many previous studies of 'essential tremor' were contaminated by cases of idiopathic or hereditary torsion dystonia. No association with Parkinson's disease was found but classical migraine occurred in approximately 26% of cases and co-segregated with tremor. The severity of arm tremor (assessed using a clinical rating scale and by scoring tremor in Archimedes spirals) and disability increased with advancing age and increasing tremor duration, but there was no correlation between age at tremor onset and either tremor severity or disability. Men and women were affected with equal severity. The sex of the affected parent had no influence on the severity of tremor or the degree of disability experienced by an affected child. Disability commenced in the second decade and progressively increased. All the index patients and 59% of the definite secondary cases had tremor induced disabilities. Eighty-five percent of index patients and 38% of secondary cases also reported some degree of social handicap. Twenty-five percent of index patients and 12% of secondary cases had been compelled to change jobs or retire. Biological fitness was normal.

One hundred and forty-seven mothers were screened for major depression at six to eight weeks post-partum. Using predetermined cut-off points, the Edinburgh Postnatal Depression Scale and the Beck scale were compared in their abilities to identify the 15% of subjects who had major depression according to DSM-III criteria. The sensitivity of Edinburgh scale was 95% and its specificity 93%. The performance of the Beck scale was markedly inferior, with a sensitivity of 68% and specificity of 88%.

PHYSIOLOGY Creatine is synthesised by the body in a two-step process (Fig. 1) involving the initial synthesis of guanidinoacetate, which takes place in the kidneys, small intestinal mucosa, pancreas, and probably the liver. The reaction between glycine and arginine is catalysed by a transamidase, which is subject to feedback inhibition by increased creatine levels. Guanidinoacetate is transported to the liver where it is methylated to creatine, which then enters the blood to be widely distributed, chiefly to muscle cells, in which it is converted to creatine phosphate-a source of high energy phosphate bonds for the immediate reformation of ATP during muscular contraction. Creatinine is formed by a spontaneous and irreversible conversion from creatine and creatine phosphate. Formation of creatinine is reasonably constant, and about 2% of whole body creatine is so transformed every 24 h. Consequently, creatinine formation also has a direct relationship to total muscle mass and roughly to the body weight. Creatinine production rate therefore remains approximately the same from day to day unless the muscle mass changes. It is not altered significantly by illness, sepsis, trauma or fever, nor by the state of hydration; however, increased protein intake can result in increases in creatinine production of the order of 10%.

BACKGROUND: Approximately half of all patients with metastatic cancer develop a malignant pleural effusion which is likely to lead to a significant reduction in quality of life secondary to symptoms such as dyspnoea and cough. The aim of pleurodesis in these patients is to prevent re-accumulation of the effusion and thereby of symptoms, and avoid the need for repeated hospitalization for thoracocentesis. Numerous clinical studies have been performed to try to determine the optimal pleurodesis strategy, and synthesis of the available evidence should facilitate this. OBJECTIVES: The aims of this review were to ascertain the optimal technique of pleurodesis in cases of malignant pleural effusion; to confirm the need for a sclerosant; and to clarify which, if any, of the sclerosants is the most effective. SEARCH STRATEGY: The Cochrane Central Register of Controlled Trials was searched for studies on 'pleurodesis'. Studies for inclusion were also identified from MEDLINE (1980 to June 2002) and EMBASE (1980 to May 2002). No language restriction was applied. SELECTION CRITERIA: RCTs of adults subjects undergoing pleurodesis for pleural effusion in the context of metastatic malignancy (or a malignant process leading to pleural effusion) were included. DATA COLLECTION AND ANALYSIS: Two reviewers independently selected studies for inclusion in the review, and extracted data using a standard data collection form. Primary outcome measures sought were effectiveness of pleurodesis as defined by freedom from recurrence of effusions, and mortality after pleurodesis. Secondary outcomes were adverse events due to pleurodesis. Dichotomous data were meta-analysed using a fixed effect model and expressed as relative risk. The number-needed-to-treat (NNT) was calculated for pleurodesis efficacy. In addition, for adverse events, the overall percentage of patients across studies exhibiting a particular adverse effect such as fever, pain, or gastrointestinal symptoms was calculated. MAIN RESULTS: A total of 36 RCTs with 1499 subjects were eligible for meta-analysis. The use of sclerosants (mitozantrone, talc and tetracycline combined)compared with control (instillation of isotonic saline or equivalent pH isotonic saline or tube drainage alone) was associated with an increased efficacy of pleurodesis. The relative risk (RR) of non-recurrence of an effusion is 1.20 (95% CI 1.04 to 1.38) in favour of the use of sclerosants based on five studies with a total 228 subjects. Comparing different sclerosants, talc was found to be the most efficacious. The RR of effusion non-recurrence was 1.34 (95% CI 1.16 to 1.55) in favour of talc compared with bleomycin, tetracycline, mustine or tube drainage alone based on 10 studies comprising 308 subjects. This was not associated with increased mortality post pleurodesis. The RR of death was 1.19 (95% CI 0.08 to 1.77) for talc compared to bleomycin, tetracycline, mustine and tube drainage alone based on six studies of 186 subjects. Death was not reported in all studies and, when reported, was attributed to underlying disease, only one death being reported as procedure-related. In the comparison of thoracoscopic versus medical pleurodesis, thoracoscopic pleurodesis was found to be more effective. The RR of non-recurrence of effusion is 1.19 (95% CI 1.04 to 1.36) in favour of thoracoscopic pleurodesis compared with tube thoracostamy pleurodesis utilizing talc as sclerosant based on two studies with 112 subjects. Comparing thoracoscopic versus bedside instillation (with different sized chest tubes) of various sclerosants (tetracycline, bleomycin, talc or mustine) the RR of non-recurrence of effusion is 1.68 (95% CI 1.35 to 2.10) based on five studies with a total of 145 participants.Adverse events were not reported adequately to enable meta-analysis. REVIEWER'S CONCLUSIONS: The available evidence supports the need for chemical sclerosants for successful pleurodesis, the use of talc as the sclerosant of choice, and thoracoscopic pleurodesis as the preferred technique for pleurodesis based on efficacy. There was no evidence for an increase in mortality following talc pleurodesis.

OBJECTIVES: While health-related stigma has been the subject of considerable research in other conditions (obesity and HIV/AIDS), it has not received substantial attention in diabetes. The aim of the current study was to explore the social experiences of Australian adults living with type 2 diabetes mellitus (T2DM), with a particular focus on the perception and experience of diabetes-related stigma. DESIGN: A qualitative study using semistructured interviews, which were audio recorded, transcribed and subject to thematic analysis. SETTING: This study was conducted in non-clinical settings in metropolitan and regional areas in the Australian state of Victoria. Participants were recruited primarily through the state consumer organisation representing people with diabetes. PARTICIPANTS: All adults aged ≥18 years with T2DM living in Victoria were eligible to take part. Twenty-five adults with T2DM participated (12 women; median age 61 years; median diabetes duration 5 years). RESULTS: A total of 21 (84%) participants indicated that they believed T2DM was stigmatised, or reported evidence of stigmatisation. Specific themes about the experience of stigma were feeling blamed by others for causing their own condition, being subject to negative stereotyping, being discriminated against or having restricted opportunities in life. Other themes focused on sources of stigma, which included the media, healthcare professionals, friends, family and colleagues. Themes relating to the consequences of this stigma were also evident, including participants' unwillingness to disclose their condition to others and psychological distress. Participants believed that people with type 1 diabetes do not experience similar stigmatisation. CONCLUSIONS: Our study found evidence of people with T2DM experiencing and perceiving diabetes-related social stigma. Further research is needed to explore ways to measure and minimise diabetes-related stigma at the individual and societal levels, and also to explore perceptions and experiences of stigma in people with type 1 diabetes.

Exosomes are nanometer-sized vesicles secreted by various cells, with potentially diverse roles in physiology. Although emphasis has been placed on their involvement in immune modulation, their potential for more wide-ranging biological effects has not been appreciated. A common exosome feature is the expression of adhesion molecules, which include the integrin family. We have for the first time addressed the possible function of B cell-derived exosome-integrins by examining adhesive interactions of exosomes (immobilized onto beads) with extracellular matrix (ECM) components and cytokine-treated fibroblasts. Integrin (beta1 and beta2) expression was demonstrated by Western blotting and flow cytometry. Binding studies (with blocking antibodies) demonstrated their function in adhesion to collagen-I, fibronectin, and tumor necrosis factor (TNF)-alpha-activated fibroblasts. Exosome adhesion to TNF-alpha-activated fibroblasts also triggered integrin-dependent changes in cytosolic calcium, measured by single cell imaging. Thus, B cell-derived exosomes express functional integrins, which are capable of mediating anchorage to ECM and cell-surface adhesion molecules, and may be a novel mode of delivering adhesion signals at distances beyond that of direct cell-cell contact during inflammation.

Journal Article LESIONS OF THE ANTERIOR FRONTAL LOBES AND DISTURBANCES OF MICTURITION AND DEFAECATION Get access JOHN ANDREW, JOHN ANDREW Form theRegional Centre for Neurosurgery, Oldchurch HospitalRomford Search for other works by this author on: Oxford Academic PubMed Google Scholar P. W. NATHAN P. W. NATHAN the National Hospital for Nervous DiseasesQueen Square, London Search for other works by this author on: Oxford Academic PubMed Google Scholar Brain, Volume 87, Issue 2, June 1964, Pages 233–262, https://doi.org/10.1093/brain/87.2.233 Published: 01 June 1964

BACKGROUND: Informal caregiving is an integral part of the care of people with severe mental illness, but the support needs of those providing such care are not often met. AIMS: To determine whether interventions provided to people caring for those with severe mental illness improve the experience of caring and reduce caregiver burden. METHOD: We conducted a systematic review and meta-analyses of randomised controlled trials (RCTs) of interventions delivered by health and social care services to informal carers (i.e. family or friends who provide support to someone with severe mental illness). RESULTS: Twenty-one RCTs with 1589 carers were included in the review. There was evidence suggesting that the carers' experience of care was improved at the end of the intervention by psychoeducation (standardised mean difference -1.03, 95% CI -1.69 to -0.36) and support groups (SMD = -1.16, 95% CI -1.96 to -0.36). Psychoeducation had a benefit on psychological distress more than 6 months later (SMD = -1.79, 95% CI -3.01 to -0.56) but not immediately post-intervention. Support interventions had a beneficial effect on psychological distress at the end of the intervention (SMD = -0.99, 95% CI -1.48 to -0.49) as did problem-solving bibliotherapy (SMD = -1.57, 95% CI -1.79 to -1.35); these effects were maintained at follow-up. The quality of the evidence was mainly low and very low. Evidence for combining these interventions and for self-help and self-management was inconclusive. CONCLUSIONS: Carer-focused interventions appear to improve the experience of caring and quality of life and reduce psychological distress of those caring for people with severe mental illness, and these benefits may be gained in first-episode psychosis. Interventions for carers should be considered as part of integrated services for people with severe mental health problems.

There has been an increase of interest in olfactory dysfunction since it was realised that anosmia was a common feature of idiopathic Parkinson's disease (PD) and Alzheimer-type dementia (AD). It is an intriguing possibility that the first sign of a disorder hitherto regarded as one of movement or cognition may be that of disturbed smell sense. In this review of PD, parkinsonian syndromes, essential tremor, AD, motor neurone disease (MND) and Huntington's chorea (HC) the following observations are made: 1). olfactory dysfunction is frequent and often severe in PD and AD; 2). normal smell identification in PD is rare and should prompt review of diagnosis unless the patient is female with tremor-dominant disease; 3). anosmia in suspected progressive supranuclear palsy and corticobasal degeneration is atypical and should likewise provoke diagnostic review; 4). hyposmia is an early feature of PD and AD and may precede motor and cognitive signs respectively; 5). subjects with anosmia and one ApoE-4 allele have an approximate 5-fold increased risk of later AD; 6). impaired smell sense is seen in some patients at 50% risk of parkinsonism; 7). smell testing in HC and MND where abnormality may be found, is not likely to be of clinical value; and 8). biopsy of olfactory nasal neurons shows non-specific changes in PD and AD and at present will not aid diagnosis.

The direct costs of care were evaluated prospectively in a sample of people with Parkinson's disease (PD) in the United Kingdom in 1998. The subjects were drawn from a random sample of general practitioner practices within a representative sample of 36 Regional Health Authorities and the equivalent. A total of 444 resource use questionnaires with usable data were returned (response rate, 59%). The total mean annual cost of care per patient for all patients by age was 5,993 pounds (9,554 euro, n = 432). Hoehn and Yahr stage significantly (P < 0.001) influenced expenditure by stage as follows: 0 and I, 2,971 pounds (4,736 euro, n = 110); II, pound 3,065 (4,886 euro, n = 89); III, 6,183 pounds (9,857 euro, n = 120); IV, 10,134 pounds (euro;16,155, n = 87); V, 18,358 pounds (29,265 euro, n = 17). National Health Service costs accounted for approximately 38% and social services for 34% of the direct costs of care. Drug expenditure accounted for 24% of overall costs in the <65 years age group and 10% in patients aged >85 years. A move from home to residential care was associated with an approximately 500% cost increase. In conclusion, PD imposes significant direct costs on public services and on individuals. These costs should be taken into account when allocating public funds.

Summary This paper reviews conceptual issues and research findings relevant to the secondary prevention of alcohol‐related problems in the primary care setting. A discussion of public health concepts and recent epidemiological studies is followed by a review of screening procedures developed to identify individuals at risk. Representative programmes designed to reduce alcohol misuse and treat harmful drinking are summarized. The results of several systematic programme evaluations suggest that modest but reliable effects on drinking behaviour and related problems can follow from brief interventions, especially with the less serious type of problem drinker. The basic elements of these interventions include information giving, brief advice, self‐help manuals, self‐help groups and periodic monitoring of progress by the health worker. It is concluded that low intensity, brief interventions have much to recommend as the first approach to the problem drinker in the primary care setting.

OBJECTIVES: While health-related stigma has been the subject of considerable research in other conditions (eg, HIV/AIDS, obesity), it has not received substantial attention in diabetes. Our aim was to explore perceptions and experiences of diabetes-related stigma from the perspective of adults with type 1 diabetes mellitus (T1DM). DESIGN: A qualitative study using semistructured interviews, which were audio recorded, transcribed and subject to thematic analysis. SETTING: All interviews were conducted in non-clinical settings in metropolitan areas of Victoria, Australia. PARTICIPANTS: Adults aged ≥18 years with T1DM living in Victoria were eligible to take part. Participants were recruited primarily through the state consumer organisation representing people with diabetes. A total of 27 adults with T1DM took part: 15 (56%) were women; median IQR age was 42 (23) years and diabetes duration was 15 (20) years). RESULTS: Australian adults with T1DM perceive and experience T1DM-specific stigma as well as stigma-by-association with type 2 diabetes. Such stigma is characterised by blame, negative social judgement, stereotyping, exclusion, rejection and discrimination. Participants identified the media, family and friends, healthcare professionals and school teachers as sources of stigma. The negative consequences of this stigma span numerous life domains, including impact on relationships and social identity, emotional well-being and behavioural management of T1DM. This stigma also led to reluctance to disclose the condition in various environments. Adults with T1DM can be both the target and the source of diabetes-related stigma. CONCLUSIONS: Stigmatisation is part of the social experience of living with T1DM for Australian adults. Strategies and interventions to address and mitigate this diabetes-related stigma need to be developed and evaluated.